3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite's life cycle. In the uncanonical N‑terminal region of the parasite enzyme, we identified several autophosphorylation sites and probed their role in activity regulation of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N‑terminus, triggered by N‑terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

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Differential effects of glycogen synthase kinase 3 (GSK3) inhibition by lithium or selective inhibitors in the central nervous system

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-013-0893-9 ◽

2013 ◽

Vol 386 (10) ◽

pp. 893-903 ◽

Cited By ~ 10

Author(s):

Laura Caberlotto ◽

Lucia Carboni ◽

Floriana Zanderigo ◽

Filippo Andreetta ◽

Michela Andreoli ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Selective Inhibitors ◽

Differential Effects ◽

The Central Nervous System

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Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2007.02.059 ◽

2007 ◽

Vol 17 (10) ◽

pp. 2863-2868 ◽

Cited By ~ 67

Author(s):

Han-Cheng Zhang ◽

Llorente V.R. Boñaga ◽

Hong Ye ◽

Claudia K. Derian ◽

Bruce P. Damiano ◽

...

Keyword(s):

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Selective Inhibitors

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Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia

Science Translational Medicine ◽

10.1126/scitranslmed.aam8460 ◽

2018 ◽

Vol 10 (431) ◽

pp. eaam8460 ◽

Cited By ~ 31

Author(s):

Florence F. Wagner ◽

Lina Benajiba ◽

Arthur J. Campbell ◽

Michel Weïwer ◽

Joshua R. Sacher ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Selective Inhibitors ◽

Acute Myeloid

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N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

10.1101/2021.06.18.448949 ◽

2021 ◽

Author(s):

Samuel Pazicky ◽

Arne Alder ◽

Haydyn Mertens ◽

D. I. Svergun ◽

Tim Gilberger ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Conformational Changes ◽

Glycogen Synthase ◽

New Drugs ◽

Glycogen Synthase Kinase ◽

Scattering Data ◽

Glycogen Synthase Kinase 3 ◽

X Ray ◽

X Ray Scattering

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite`s life cycle. Here, we show that PfGSK3 exhibits autophosphorylation, leading to an extensive phosphorylation both in vitro and in the parasite. In the uncanonical N-terminal region of the parasite enzyme, we identified several autophosphorylation sites that regulate the activity of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N-terminus, triggered by N-terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

Download Full-text